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EP0984901A1 - Hydroxylapatite gel - Google Patents

Hydroxylapatite gel

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Publication number
EP0984901A1
EP0984901A1 EP19980934899 EP98934899A EP0984901A1 EP 0984901 A1 EP0984901 A1 EP 0984901A1 EP 19980934899 EP19980934899 EP 19980934899 EP 98934899 A EP98934899 A EP 98934899A EP 0984901 A1 EP0984901 A1 EP 0984901A1
Authority
EP
Grant status
Application
Patent type
Prior art keywords
hydroxylapatite
gel
ƒ
bone
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP19980934899
Other languages
German (de)
French (fr)
Other versions
EP0984901B1 (en )
Inventor
Andrey Ivanov Andreev
Arnulf-Univ. Klinik für Mund- Kiefer AKH BAUMANN
Dimitar Assenov Djerov
Sava Assenov Dramov
Rolf Ewers
Emil Stoimenov Ivanov
Margarita Nikolova Jordanova
Gueorgui Nikolov Kirov
Else Spassova
Kiril Ranguelov Tchakalski
Velitchka Alexandrova Velichkova
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ewers Rolf Prof Dr Dr
Original Assignee
Ewers Rolf Prof Dr Dr
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date

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Classifications

    • CCHEMISTRY; METALLURGY
    • C04CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
    • C04BLIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
    • C04B35/00Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products
    • C04B35/01Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics
    • C04B35/447Shaped ceramic products characterised by their composition; Ceramics compositions; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products based on oxide ceramics based on phosphates, e.g. hydroxyapatite
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02Inorganic materials
    • A61L27/04Metals or alloys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02Inorganic materials
    • A61L27/12Phosphorus-containing materials, e.g. apatite
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28Materials for coating prostheses
    • A61L27/30Inorganic materials
    • A61L27/32Phosphorus-containing materials, e.g. apatite
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00Phosphorus; Compounds thereof
    • C01B25/16Oxyacids of phosphorus; Salts thereof
    • C01B25/26Phosphates
    • C01B25/32Phosphates of magnesium, calcium, strontium, or barium
    • C01B25/325Preparation by double decomposition
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005The prosthesis being constructed from a particular material
    • A61F2310/00179Ceramics or ceramic-like structures
    • A61F2310/00293Ceramics or ceramic-like structures containing a phosphorus-containing compound, e.g. apatite
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389The prosthesis being coated or covered with a particular material
    • A61F2310/00592Coating or prosthesis-covering structure made of ceramics or of ceramic-like compounds
    • A61F2310/00796Coating or prosthesis-covering structure made of a phosphorus-containing compound, e.g. hydroxy(l)apatite

Abstract

The invention relates to a hydroxylapatite gel obtained through a sol-gel process, in which an alkaline aqueous solution of a calcium slat is reacted with an alkaline aqueous solution of a phosphate salt in a calcium and phosphorus molar ratio in the range of 1.67 to obtain a sol. The sol in then transformed into a gel by hydrothermal treatment. The hydroxylapatite gel thus obtained exhibits excellent properties for use as a binding agent in moldable hydroxylapatite materials, comprising a granular filling material containing calcium in addition to the gel. The filling material is also preferably a hydroxylapatite material. Shaped bodies can be obtained from the hydroxylapatite material, which are most suitable for use in bone surgery and as filtering materials. The invention further relates to a metal implant comprising a coating of the inventive hydroxylapatite material. The invention also concerns a method for producing the hydroxylapatite gel, the shaped bodies and the coated metal implant.

Description

Hydroxylapatite gel

The invention relates to a hydroxylapatite gel, this containing masses and moldings as well as their use, especially in the field of bone surgery.

In the field of bone surgery is a need for bone substitutes and implants which korpervertraglich and easy to work s nd. In order to facilitate the growth in the body, the bone graft should have a structure that is similar to the bone as possible. In addition, a high mechanical stability is desirable. The implant material should also be suited as carriers for drugs such as growth promoting or-inhibiting substances.

As a bone substitute material, a hydroxylapatite Mateπal nat preserved, which is obtained from the calcium carbonate skeleton of calcareous algae. Such a material is m DE 37 09 897 C2. pern for the preparation of the granular hydroxyapatite Formkor- Mateπal obtained by hydrothermal synthesis is emgeruttelt with slaked lime as a binder m a molded article and then again subjected to a hydrothermal treatment. The bone implant thus obtained has a high mterkonnektive porosity and a high specific surface. In his chemistry and crystalline structure, it is much more similar to bone than others KnochenersatzmaterIallen.

In some special applications, however, bone replacement materials are required which have an even higher porosity and particularly high mechanical stability. T ASK of the invention is to provide materials which are suitable for producing a bone substitute material which m its chemical composition and crystalline structure of natural bone is as similar as possible, has a very porous microstructure, but it has a high mechanical stability. The materials should be easy to manufacture, inexpensive and easy to process. In addition, they should make it possible to adjust the targeted Kπstallphasen portion and the strength of the bone substitute material during processing.

The solution of this object is achieved by the hydroxyapatite gel according to claim 1. This hydroxylapatite gel is an essential component of the moldable hydroxylapatite composition as claimed in claim 9 and the compacted hydroxylapatite composition as claimed in claim 15, which in turn according to constituent of the inventive hydroxyapatite-shaped body claim 16 is. The invention further relates to the use of hydroxyapatite-molded article according to claim 17. The molded article is also hydroxyapatite as .Beschichtung m a metal implant according to claim 20 is present. Moreover, the invention relates to a method for producing the metal implant according to claim 21, a method for preparing the hydroxylapatite gel according to claim 23 and a method for manufacturing the hydroxyapatite-molded article according to claim 28th

Further process variants and embodiments are evident from the dependent claims.

In a first aspect the invention relates to a hydroxylapatite gel which is obtainable by a sol-gel process. In this case, an alkaline aqueous solution of a calcium salt with an alkaline aqueous solution of a phosphate salt is first converted to a sol. The stoichiometry is chosen so that the ratio of calcium to phosphorus ratio corresponds to the hydroxyapatite. Thus, the molar ratio of calcium to phosphorus in the sol preparation in the range of about 1.67. Then, the resultant sol is converted by hydrothermal treatment into a gel.

The pH in the sol preparation is preferably in a range of 9 bis 12, particularly advantageously between 10.5 and 11. The desired pH range can be adjusted by the addition of the usual bases. Particularly suitable for this is ammonia. It has' .zudem been found to be advantageous to first adjust both aqueous solutions separately to the desired pH value and to bring the pH, if necessary, after mixing both solutions again in the desired range.

Advantageously, the sol-production is carried out in a temperature range between 10 ° and 40 ° C, particularly advantageously at room temperature (20 ° to 25 ° C).

In the preparation of the sol, for example, 0.1 to IN aqueous solutions of the calcium salt and the phosphate salt can be used. Particularly suitable are 0.3 to 0.5N aqueous' solution of the salts.

As raw materials all the soluble calcium and phosphate salts can be used, which should preferably not contain körperunverträglichen ingredients. A suitable calcium salt is, for example Calciu nitrate. As diammonium phosphate salt can be used.

Under the conditions mentioned, the sol forms after mixing the two aqueous solutions by allowing to stand for a period of several days. In a second step, the sol is converted by hydrothermal treatment into a gel. The hydrothermal treatment is advantageously carried out in a temperature range of 180 to 200 ° C. Particularly advantageously it is carried out in an autoclave. Particularly suitable are coated with polytetrafluoroethylene or similar inert linings autoclave. It is advantageous to fill the autoclave maximum of two-thirds and the hypo- drothermale treatment under the then adjusting Satti- the solution supply steam pressure through feeds is. The pH in the reaction to the gel is advantageously in the same range as in the sol preparation, between 9 and 12 and more particularly between 10.5 and 11. FIG.

During the hydrothermal treatment, are formed in sol seed crystals and fine crystals of hydroxyapatite. Depending on the duration of the hydrothermal treatment of the sol, the ray crystal phase proportions in the hydroxyapatite gel can be selectively controlled. In this way, the physical properties of hydroxyapatite gel can be influenced. Advantageously, the hydrothermal treatment takes place until the proportion of crystal nuclei and microcrystalline hydroxylapatite in the gel than 80% and in particular amounts to about 90%. In the gel mass up to two thirds of the water contained in the sol retained. Usually, the gel contains erfmdungsgemaße after its manufacture up to 70 wt .-% water. A mid-water support located at about 60 wt .-%. Let be the hydroxylapatite gel stand for a long time, the gel settles and it makes a s ch 'aqueous supernatant. By decanting the supernatant of this, the water content of the gel let, if desired, reducing a targeted manner.

The erfmdungsgemaße hydroxylapatite gel is excellent as a binder and can be used for example in the production of bone substitute materials and Filtermateπalien. Compared to conventional binders, the inventions dungsgemaße hydroxyapatite gel has the advantage that the time set in its production phase crystal structure is retained in the final product and final materials are obtained krostruktur with a very porous micro. In addition, the erfmdungsgemaße hydroxylapatite gel for an excellent moldability of it containing compositions whose density can be influenced by compressing provides.

In another aspect, the invention relates to a moldable hydroxylapatite composition, which comprises a calcium-containing granular filler next to the erf dungsgemaßen hydroxylapatite gel which acts as a binder. Suitable fillers are, for example, all those which are already being used in the field of bone surgery. Particularly suitable as granular filler is hydroxyapatite Mateπalien, which are obtained from kalkmkrustierenden algae. Examples are described in German Patent 37 09 897th In the materials described therein, the calcium carbonate skeleton of the algae is maintained, so that the material has a high porosity and a large specific mterkonnektive surface.

As a granular filler for the moldable hydroxylapatite composition and a modified, tricalcium phosphate-containing hydroxylapatite material can be used, which is obtainable by reacting an organic compounds liberated from hard algae tissue of an alkaline aqueous phosphate solution with addition of Mg 2+ ions at elevated temperature. Such a material is described in a parallel German patent application of the applicant. This tricalcium phosphate-containing hydroxylapatite material advantageously has a Tr - calcium phosphate content of 20 to 90 wt% to.. The seaweed is hard tissue, such as in the case of hydroxyapatite nichtmodiflzierten Mateπalien, advantageously obtained from lime-encrusting sea algae, in particular those of the species or Corallinacea Codiacea.

In the moldable hydroxylapatite composition erfmdungsgemaße the hydroxyapatite gel and the granular solid can be mixed in a wide ratio. Suitable examples are Gewichtsverhaltnisse of hydroxylapatite gel and granular solid is between 10: 1 and 1:10, it being understood here by a hydroxylapatite gel with a water content of about 60 wt .-%. The respective proportions are chosen according to the desired use of the erf spateren dungsgemaßen moldable hydroxylapatite composition. The manner in which the moldable material to be processed, plays a role in selecting the proportions of the two components. In the use of the inventive moldable hydroxyl apatite material for a coating higher levels of gel can facilitate processing. Moldings mainly from hydroxylapatite composition - for example, bone substitute materials must have a high mechanical strength - usually contain a higher proportion of granular solids. 8 can be used: the latter are for example Gewichtsverhaltnisse from gel to solid of between 1: 5 and the first

The erfmdungsgemaße moldable hydroxylapatite composition may contain other components as are customary in bone substitute materials or filter materials. For bone replacement material may for example be expedient for the mass to add at least one active ingredient. Examples include growth promoting or-inhibiting substances. Specific examples include antibiotics, chemotherapeutic agents, anti-tumor compounds and bone substances. Examples of the latter bone morphogenic proteins can be called (bone morphogenic proteins). These agents can be incorporated erfmdungsgemaße mass m, or they are applied to the finished, molded article produced from the inventive shaped mass. Suitably each clinically active set is used for each active ingredient.

The erfmdungsgemaße moldable hydroxylapatite composition is inventive shaped by their share. Hydroxylapatite gel arbitrarily malleable. This greatly facilitates the production of even complicated moldings constructed. When a product obtained from algae kalkmkrustierenden hydroxyapatite material is used as granular filler, a moldable mass is obtained, which consists virtually exclusively of hydroxyapatite. The moldings produced from this mass are not only extremely korpervertraglich, but they also have an unusually porous microstructure with high mechanical stability. The erfmdungsgemaße hydroxylapatite composition is therefore extremely well suited for the production of bone replacement materials. In addition, the physical properties of the moldable material and consequently the moldings produced therefrom can specifically influence. For instance, it is possible to compress the hydroxylapatite composition under pressure and thus to increase its density and its firmness. Turning to compress a pressure which does not exceed 1 MPa, the porous microstructure of the mass is retained.

To control the crystal phase proportions in the gel - and thus m of the gel containing moldable hydroxylapatite composition - had already been pointed out. The Kristallmitat can be influenced by the type and duration of the thermal treatment of the moldable hydroxylapatite composition further with a solid molded article produced from the composition.

For this purpose the erfmdungsgemaße moldable hydroxylapatite composition is filled m a suitable shape and suitably first degassed before has hardened,. is suitable for this purpose, for example a treatment by ultrasound. In order to achieve a higher density and higher strength, the moldable material, as mentioned, be compressed. The thermal treatment for the mass has hardened, is advantageously carried out in a temperature range between 500 ° and 650 ° C, in particular between 550 ° and 600 ° C. The duration of the thermal treatment depends on the composition of the body of the moldable material and the size of the mold. Usually, the time of treatment is between about half an hour to several hours will be. If necessary, the molded article produced can erfmdungsgemaße post-processed using conventional surgical tools and to be brought its definitive m ¬ term form. In addition, coatings may as such be applied from bone inductive connections that have already been mentioned on the inventive shaped hydroxylapatite moldings.

Because of the very porous microstructure with high mechanical strength, the molded article is excellent erfmdungsgemaße hydroxyapatite for use in the field of bone surgery, in particular as bone substitute material or as carrier material for active substances. Because of their porous structure, the inventive shaped bodies can also be used as filter materials.

The inventive shaped hydroxyapatite molded article are also useful as bioactive coating on metal implants and, in particular titanium bone implants. The invention relates in a further aspect, such a metal implant comprising a coating of the hydroxylapatite inventive shaped molded article. To prepare the implant a layer of of the inventive moldable hydroxylapatite composition is applied, and this subjected to a thermal treatment between 500 ° and 650 ° C, as described above to the metal surface. In order to improve the adhesion of the coating on the metal surface, this surface is treated appropriately prior to coating. Such treatments are known to improve adhesion to metal implants. These known surface treatment processes can be applied prior to application of the inventive coating. However, a treatment is preferably carried out, which is also the subject of this invention.

In the preferred inventive shaped process for producing a metal implant, the surface of the metal m is an electrolyte solution with spark discharge at a temperature between -10 and -20 ° C diert oxy before applying the coating until the thickness of the oxide layer between 25 and 40 microns amounts. The oxidation takes place in alternating current of 50 Hz at a voltage of 110-200 V. The aqueous electrolyte solution used comprises:

Polyethylene glycol (molecular weight ¬ 200 to 400) 80 to 200 ml / 1

At least one Chlorsauerstoff- 5 to 20 g / 1 acid or its salt

as and or

Hydrofluoric acid or salts thereof 2 to 25 g / 1 and / or

Phosphoric acid or salts thereof 20 to 80 g / 1 and / or

Perborsaure or salts thereof 10 to 40 g / 1

As an oxidizing agent, the alkali metal salts of chlorine-oxygen acids are preferably used here in particular chlorates and Chloπte as sodium chlorate or Natriumchloπt. It can also be used mixtures of different salts. Of the other acids, preferably the alkali metal or ammonium salts. Examples of preferred compounds are Natriumflu- ORID, Am onium fluoride, potassium and sodium.

As Amm functional aliphatic alcohol nurse or nurse be used, preferably Triethylamm or Tπethanolamm.

The oxide layer obtained according to the inventive shaped procedure is then recrystallized m a firing process. Slightly expedient, the oxide layer is exposed after drying for 20 to 40 minutes a temperature of 550 to 650 ° C. Advantageously, the still located on the oxide layer may unbound ions are removed with distilled water before the erf dungsgemaße moldable material is applied to the treated metal surface. Suitably, the layer thickness amounts to 5 to 10 μ. The thermal treatment of the mouldable mass is carried out as described above.

The invention will be explained below with some examples closer. example 1

Preparation of hydroxyapatite gel

A 0.5N aqueous solution of Ca (N0 3) 2 • 4H 2 0 and a 0.3N aqueous solution of (NH 4) 2 HP0 4 are set separately from each other with ammonia to a pH of 10.5. Both solutions are in relation -.1: 1 thoroughly mixed with stirring. The pH of the solution thus obtained is brought again if necessary with ammonia to 10.5.

The reaction mixture is allowed to stand at a temperature of between 20 ° and 25 ° C for five to six days. During this time, a primary apatite sol forms.

To produce a gel the sol is hydrothermally treated at 180 to 200 ° C. For this purpose the gel is transferred to a PTFE-lined autoclave, which is filled to a maximum of two thirds. The hydrothermal treatment is carried out under the saturated vapor pressure of the solution. The treatment is continued until at least 80% and fine crystal nuclei -kristalliner hydroxyapatite have formed. Preferably, the hydrothermal treatment is continued until about 90% of seed crystals and fine crystalline hydroxyapatite have formed. The hydrothermal treatment usually requires at least 24 hours. After about 30 hours of reaction time no significant change in crystallinity more can be observed. The obtained hydroxyapatite gel has a water content of about 60 wt .-%.

example 2

Preparing a moldable hydroxylapatite composition

Obtained in Example 1 hydroxylapatite gel is mixed with a according to German Patent 37 09 897 granular hydroxylapatite material obtained from calcareous red algae in a weight ratio of 1:10. This gives a homogeneous dough-like mass.

example 3

Producing a hydroxylapatite molded article

Obtained in Example 2 hydroxylapatite composition is filled into a mold. It is vented by exposure to ultrasound and compressed for a few minutes at a pressure of 0.9 MPa. Subsequently, the compacted mass is thermally treated in the mold in an oven at 550 to 600 ° C for about 60 minutes. In this way, a shaped body is obtained with a very porous microstructure, and high mechanical strength. He can be reworked mechanically.

example 4

-Manufacture of a hydroxyapatite-coated metal implant

1. Pretreatment of the metal implant

A titanium bone implant is oxidized by spark discharge in an electrolyte solution at -10 ° C. The solution includes:

Polyethylene glycol (MG 200) 100 ml / 1

Sodium chlorate / chlorite 5 g / 1

Sodium fluoride 21 g / 1

Potassium dihydrogen phosphate 68 g / 1

10 ml of triethylamine / 1 V The oxidation is carried out for 5 minutes at a voltage of 160th Then, the treated implant is removed from the solution, and the oxide layer formed is recrystallized for twenty minutes in an oven at 600 ° C. It is then rinsed several times with boiling distilled water until all unbound ions are completely removed from the implant.

2. Pretreatment of the metal implant (Option 2)

The surface of the titanium bone implant is oxidized with spark discharge in an electrolyte solution at -15 ° C. The solution consists of:

Polyethylene glycol (MG 400) 150 ml / 1

Sodium chlorate / chlorite 10 g / 1

Sodium fluoride 21 g / 1

Potassium dihydrogen phosphate 68 g / 1

'Sodium perborate 38 g / 1

Ammonium fluoride 6 g / 1

Triethanolamine 15 ml / 1

The implementation of the method as in 1, but at a voltage of 180 V for 3.5 minutes. recrystallization of the oxide layer is carried out analogously to item 1 at 580 ° C for 30 minutes. The post-treatment also corresponds to point first

3. Application of the coating

The treated according to item 1 or 2 metal implant is provided with a coating consisting of a prepared according to Example 1 and a hydroxylapatite gel according to German Patent 37 09 897 schem produced hydroxyapatite granules in a volume ratio of 2: 0.75. The layer thickness is about 7 μ. After drying the layer, it is fixed for 40 minutes in an oven at 550 ° C.

4. Application of the coating (Variant 2)

The procedure is as described under '.Peer 3, but the ratio of hydroxylapatite gel into granules 2: 1. The fixing of the layer is carried out for 30 minutes at 500 ° C.

In both cases, a coating with exceptionally good bioactive properties is obtained. The coating is well connected with the metal surface. The inventive coated metal implant resulted in clinical studies extremely favorable conditions for bone augmentation and a good attachment of the bone tissue newly formed on the surface.

Claims

Patentanspr├╝che
1. hydroxylapatite gel, erhältlich by a sol-gel Prozeß, characterized in that an alkaline daß wässrige solution of a calcium salt with an alkaline wässrigen solution of a phosphate salt with a molar Verhältnis of calcium are converted to phosphorus in the range of 1.67 to give a sol and the sol is converted by hydrothermal treatment m a gel.
2. hydroxylapatite gel gemäß claim 1, characterized in that the pH in the sol preparation daß m a range from 9 to 12 and is in particular 10.5 to 11.
3. hydroxylapatite gel gemäß claim 1 or 2, characterized in that daß the sol preparation in 10°C to 40°C unc carried to 25°C particularly in 20°C.
4. hydroxylapatite gel gemäß one of Ansprüche 1 to 3, characterized in that daß 0, 1 to IN wässrige solutions of the calcium salt and the phosphate salt and, in particular 0.3 to 0.5 N w ässrige solutions are used.
5. hydroxylapatite gel gemäß one of Ansprüche 1 to 4, characterized in that daß as calcium salt is calcium nitrate is used.
6. hydroxylapatite gel gemäß one of Ansprüche 1 to 5, characterized in that is used as daß diammonium hydrogen phosphate salt.
7. hydroxylapatite gel gemäß one of Ansprüche 1 to 6, characterized in that the hydrothermal treatment is carried out to 180°C daß 200°C.
8. hydroxylapatite gel gemäß claim 7, characterized in that the hydrothermal treatment daß takes place until the proportion of crystal nuclei and microcrystalline hydroxylapatite über 80% and particularly about 90% beträgt.
9. A moldable hydroxylapatite composition, characterized in that they daß the hydroxyapatite gel gemäß Ansprüche one of 1 to 8 and a calcium-containing granulären Füllstoff umfaßt.
10. A moldable hydroxylapatite composition gemäß claim 9, characterized daß serves as granulärer Füllstoff a product obtained from calcareous algae hydroxylapatite material.
11. A moldable hydroxylapatite composition gemäß claim 10, characterized in that daß as granulärer Füllstoff serves containing hydroxylapatite material which is erhältlich by reacting a liberated from organic compounds algae tricalcium phosphate -Hartgewebes in an alkaline wässrigen phosphate Lösung with addition of Mg 2+ ions at erhöhter temperature.
12. A moldable hydroxylapatite composition gemäß claim 11, characterized in that the tricalcium phosphate content from 20 to 90 daß wt.%, Based on the granulären Füllstoff, beträgt.
13. A moldable hydroxylapatite composition gemäß one of Ansprüche 9 to 12, characterized in daß hydroxylapatite gel and granulärer Füllstoff in a weight Verhältnis from 10: 1 to 1:10 and especially from 1: 5 to 1: 8 are found.
14. A moldable hydroxylapatite composition gemäß one of Ansprüche 9 to 13, characterized by a content of at least one agent, in particular a wachstumsfördernden or growth-inhibiting compound, an antibiotic, a chemotherapeutic agent, a tumor-inhibiting compound or a bone-inductive compound, in particular at least one bone morphogenic protein.
15. Compacted hydroxylapatite composition, erhältlich by compression of the moldable hydroxylapatite composition gemäß Ansprüche one of 9 to 14 at a pressure of up to 1 MPa.
16. hydroxylapatite Formkörper, erhältlich by thermal treatment of the hydroxylapatite composition gemäß Ansprüche one of 9 to 15 at a temperature of 500°C to 650°C and in particular from 550 °C to 600°C.
17. The use of the hydroxylapatite gemäß molded article of claim 16 in bone surgery, in particular as bone substitute material or as Trägermaterial für active ingredients, and as filter material.
18. The use of the hydroxylapatite molded article gemäß claim 17 as Trägermaterial für wachstumsfördernde or growth-inhibiting compounds, an antibiotic, a chemo therapeutic agent, a tumor-inhibiting compound or a bone-inductive compound, in particular at least one bone morphogenic Protein.
19. Use gemäß claim 17 or 18 as bioactive coating on metal implants and, in particular titanium bone implants.
20. Metal implant, in particular titanium bone implant, characterized in that it daß a coating of the hydroxylapatite Formkörper gemäß claim 16 umfaßt.
21. A method for producing a metal implant, in particular a titanium bone implant, gemäß claim 20, characterized in that the daß Oberfläche of the metal implant a layer of the moldable hydroxylapatite composition gemäß one of Ansprüche 9 to 14 and applied it to a thermal treatment at a temperature between 500°C and 650°C is subjected.
22. The method gemäß claim 21, characterized in that the daß Oberfläche of the metal implant prior to application of the coating in an electrolyte solution with spark discharge at a temperature between -10°C and -20°C is oxidized, until the thickness of the oxide layer between 25 and 40 beträgt μm, wherein the oxidation at alternating current of 50 Hz is carried out at a voltage of 110 V to 200 V in an electrolyte solution, which umfaßt: polyethylene glycol (molecular weight 200 to 400) 80 to 200 ml / Chlorsauerstoffsäure 1 at least one or a salt thereof 5 to 20 g / 1, and
Amine 10 to 30 ml / 1 and / or
Flußsäure or salts thereof 2 to 25 g / 1 and / or
Phosphorsäure or salts thereof 20 to 80 g / 1 and / or Perborsäure or salts thereof 10 to 40 g / 1
23. A method for preparing the hydroxylapatite gel gemäß one of Ansprüche 1 to 8, characterized in that an alkaline daß wässrige Lösung of a calcium salt with an alkaline wässrigen Lö are reacted solution of a phosphate salt with a molar Verhältnis of calcium to phosphorus in the range of 1.67 to give a sol and the sol is converted by hydrothermal treatment into a gel.
24. The method gemäß claim 23, characterized in that daß the pH in the sol preparation in a range from 9 to 12 and in particular from 10.5 to. 11
25. The method gemäß claim 23 or 24, characterized in that the hydrothermal treatment at daß 180°C carried to 200°C.
26. The method gemäß one of Ansprüche 23 to 25, characterized in that the hydrothermal treatment in an autoclave daß, in particular a polytetrafluoroethylene-lined autoclave, occurs.
27. The method gemäß claim 26, characterized in that the autoclave daß to a maximum of two thirds is gefüllt.
28. A method for producing a molded article hydroxylapatite gemäß claim 16, characterized g e. indicates a calcium-daß granulärer Füllstoff and Hydroxylapatitgel gemäß Ansprüche one of 1 to 9 are mixed together and a thermal treatment at a temperature of 500°C to 650°C be subjected and in particular to 550°C 600°C.
29. The method gemäß claim 28, characterized in that the daß hydroxylapatite composition before the thermal treatment is degassed and degassed in particular by means of ultrasonic irradiation.
30. The method gemäß claim 28 or 29, characterized in daß the hydroxylapatite composition is compressed before the thermal treatment.
31. The method gemäß claim 30, characterized in that the Formkörper daß in a Preßform at a pressure of up to 1 MPa is handled.
EP19980934899 1997-05-30 1998-05-26 Hydroxylapatite gel Active EP0984901B1 (en)

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BG10154497 1997-05-30
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DE59809162D1 (en) 2003-09-04 grant
US6428803B1 (en) 2002-08-06 grant
ES2209166T3 (en) 2004-06-16 grant
EP0984901B1 (en) 2003-07-30 grant
WO1998054089A1 (en) 1998-12-03 application
CA2291677A1 (en) 1998-12-03 application

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